Dnmt3L and the Establishment of Maternal Genomic Imprints

TLDR

Genomic imprinting silences complementary gene sets in male and female gametes. Dnmt3L is expressed during gametogenesis and is essential for establishing maternal genomic imprints; its loss causes male infertility, embryonic lethality, loss of methylation at imprinted loci, biallelic expression of normally paternally expressed genes, and indicates that Dnmt3L functions as a regulator rather than a catalytic methyltransferase.

Abstract

Complementary sets of genes are epigenetically silenced in male and female gametes in a process termed genomic imprinting. The Dnmt3L gene is expressed during gametogenesis at stages where genomic imprints are established. Targeted disruption of Dnmt3L caused azoospermia in homozygous males, and heterozygous progeny of homozygous females died before midgestation. Bisulfite genomic sequencing of DNA from oocytes and embryos showed that removal of Dnmt3L prevented methylation of sequences that are normally maternally methylated. The defect was specific to imprinted regions, and global genome methylation levels were not affected. Lack of maternal methylation imprints in heterozygous embryos derived from homozygous mutant oocytes caused biallelic expression of genes that are normally expressed only from the allele of paternal origin. The key catalytic motifs characteristic of DNA cytosine methyltransferases have been lost from Dnmt3L, and the protein is more likely to act as a regulator of imprint establishment than as a DNA methyltransferase.